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Clin Cancer Res. 2014 Aug 1;20(15):4129-40. doi: 10.1158/1078-0432.CCR-13-3036. Epub 2014 Jun 4.

Next-generation sequencing of translocation renal cell carcinoma reveals novel RNA splicing partners and frequent mutations of chromatin-remodeling genes.

Author information

1
Departments of Medical Oncology and ntannir@mdanderson.org gabriel.malouf@psl.aphp.fr.
2
Bioinformatics and Computational Biology and.
3
Genitourinary Medical Oncology.
4
Pathology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Faculty of Medicine Pierre et Marie Curie, Institut Universitaire de Cancérologie GRC5, University Paris 6;
5
Department of Genetics, Institut Curie;
6
Department of Pathology, Hôpital Saint Joseph, Paris;
7
Department of Medical Oncology, Institut Gustave Roussy, Villejuif;
8
Centre de Pathologie, Amiens, Picardie, France; Departments of.
9
DNA Analysis Facility, Department of Genetics.
10
Departments of Medical Oncology and.
11
Division of Surgery, Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and.
12
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
13
Genitourinary Medical Oncology, ntannir@mdanderson.org gabriel.malouf@psl.aphp.fr.

Abstract

PURPOSE:

MITF/TFE translocation renal cell carcinoma (TRCC) is a rare subtype of kidney cancer. Its incidence and the genome-wide characterization of its genetic origin have not been fully elucidated.

EXPERIMENTAL DESIGN:

We performed RNA and exome sequencing on an exploratory set of TRCC (n = 7), and validated our findings using The Cancer Genome Atlas (TCGA) clear-cell RCC (ccRCC) dataset (n = 460).

RESULTS:

Using the TCGA dataset, we identified seven TRCC (1.5%) cases and determined their genomic profile. We discovered three novel partners of MITF/TFE (LUC7L3, KHSRP, and KHDRBS2) that are involved in RNA splicing. TRCC displayed a unique gene expression signature as compared with other RCC types, and showed activation of MITF, the transforming growth factor β1 and the PI3K complex targets. Genes differentially spliced between TRCC and other RCC types were enriched for MITF and ID2 targets. Exome sequencing of TRCC revealed a distinct mutational spectrum as compared with ccRCC, with frequent mutations in chromatin-remodeling genes (six of eight cases, three of which were from the TCGA). In two cases, we identified mutations in INO80D, an ATP-dependent chromatin-remodeling gene, previously shown to control the amplitude of the S phase. Knockdown of INO80D decreased cell proliferation in a novel cell line bearing LUC7L3-TFE3 translocation.

CONCLUSIONS:

This genome-wide study defines the incidence of TRCC within a ccRCC-directed project and expands the genomic spectrum of TRCC by identifying novel MITF/TFE partners involved in RNA splicing and frequent mutations in chromatin-remodeling genes.

PMID:
24899691
PMCID:
PMC4167829
DOI:
10.1158/1078-0432.CCR-13-3036
[Indexed for MEDLINE]
Free PMC Article

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